The present invention relates to a process for the manufacture of hydroxymethylimadazoles. More particularly, this invention relates to a new and improved process for the manufacture of hydroxymethylimadazoles of formula I ##STR1## wherein R.sub.1 is hydrogen, a loweralkyl, cycloalkyl, aryl or aralkyl which is located on any one of the two nitrogen atoms in the imidazole nucleus; and R.sub.2 and R.sub.3 are independently hydrogen, a loweralkyl, cycloalkyl, aryl and aralkyl, as well as inorganic and organic acid addition salts thereof.
As used herein the term "loweralkyl" means both a straight and branched chain C.sub.1 -C.sub.6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, t-pentyl, neopentyl, n-hexyl and the like).
The term "cycloalkyl" means a cycloalkyl having a 3 to 6 membered ring(e.g., cyclopropyl, cyclopentyl, cyclohexyl and the like).
The term "aryl" means phenyl, a phenyl optionally substituted by one or more radicals selected from the group consisting of a C.sub.1 -C.sub.6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, t-pentyl, neopentyl, n-hexyl and the like), halogen (e.g., chlorine, bromine, fluorine), a C.sub.1 -C.sub.6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy and the like), trifluoromethyl, nitro and cyano, or naphthyl group.
The term "aralkyl" means phen(C.sub.1 -C.sub.3)alkyl, in which the phenyl nucleus may be substituted by one or more radicals selected from the group consisting of a C.sub.1 -C.sub.6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-pentyl, n-pentyl, isopenyl, t-butyl, neopentyl, n-hexyl and the like), halogen (e.g., chlorine, bromine and fluorine), a C.sub.1 -C.sub.6 alkoxy, (e.g., methoxy, ethoxy, propoxy, isopropoxy and the like), trifluoromethyl, nitro and cyano, or naphthyl group.
Certain hydroxymethylimidazoles of formula I are known compounds and are useful as starting materials for the preparation of therapeutically valuable N"-cyano-N-methyl-N'-{2-[(5-methylimidazol-4-yl)methylthio]ethyl} guanidines (See J. Med. Chem. 20,901,1977), one of which is known generically as cimetidine and has been therapeutically used in the treatment of duodenal ulcer and pathological hypersecretory conditions.
Hydroxymethylimadazoles of the types described herein have been prepared by a variety of means known to the prior art.
In one prior art process described in J. Amer. Chem. Soc. 71,2444,1949, the hydroxymethylimidazoles are prepared by reducing an imidazolecarboxylic acid ester with LiAlH.sub.4 under anhydrous conditions. A similar process is described in J. Med. Chem. 20,901,1977 and British Pat. No. 1,338,169 and is hereinafter referred to as Method A.
In yet another prior art process disclosed in German OLS No. 2,637,670, the hydroxymethylimidazoles are prepared by reducing an imidazolecarboxylic acid ester with a combined use of an alkali metal and liquid ammonia under anhydrous conditions and is hereinafter referred to as Method B.
In German OLS No. 2,538,621, a process is disclosed for producing the hydroxymethylimidazoles by electrochemical reduction of an imidazolecarboxylic acid ester and is hereinafter referred to as Method C.
Another process of the prior art for the production of hydroxymethylimidazoles involves hydroxymethylation of an imidazole with formaldehyde under pressure and is hereinafter referred to as Method D. (See J. Chem. Soc. 99,2052,1911; and ibid 3128,1927).
The prior art processes described above have certain inherent disadvantages. For instance, Method (A) involves the use of an expensive and hazardous LiAlH.sub.4 as a reducing agent. Additionally, the reaction must be carried out in a substantially anhydrous environment.
Method (B) again involves the use of a hazardous alkali metal. Furthermore, this process involves the use of liquid ammonia in which the reaction is conducted at extremely low temperatures, such as -70.degree. C., so that the process requires special equipment and therefore is not economically attractive for industrial application.
In commercialization of Method (C), substantial capital investment is required to obtain an expensive electrolyzer. Therefore, this method again is not economically attrative.
Method (D) suffers from several disadvantages, including a very low yield of the final products, difficulty in separation of the starting material from the final product produced and the need for application of high pressure.
It is therefore an object of the present invention to overcome these disadvantages associated with the prior art processes.
It is another object of this invention to provide a process for the production of hydroxymethylimidazoles in an aqueous medium.
It is a further object of this invention to provide a simple and economical process for the production of hydroxymethylimidazoles.
Now we have unexpectedly and surprisingly discovered a process for the manufacture of hydroxymethylimidazoles of formula I, which comprises reacting a compound of formula II ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 are as defined above and R.sub.4 is hydrogen or a C.sub.1 -C.sub.6 alkyl, with a formaldehyde agent in the presence of an alkali in an aqueous medium, or treating a compound of formula III ##STR3## wherein R.sub.1, R.sub.2 and R.sub.3 are as defined above and X is an alkali cation with a formaldehyde agent in an aqueous medium and, if appropriate, in the presence of an alkali.
In accordance with the process of the present invention, the compounds of formula I can be converted, if desired, to inorganic and organic acid addition salts. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid and the like. Suitable organic acids include picric acid, fumaric acid, maleic acid, pamoic acid, p-toluenesulfonic acid and the like.
Suitable formaldehyde agents or sources of formaldehyde for use in the process of the present invention include aqueous formaldehyde, paraformaldehyde and formaldehyde alkali metal bisulfites.
Suitable alkalies include the hydroxides, carbonates and bicarbonates of alkali metal and the hydroxides, oxides and carbonates of alkali earth metal. Representive alkalies are sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, calcium oxide, barium oxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
Suitable alkali cations include alkali metal and alkali earth metal cations, such as sodium, potassium, lithium, barium and calcium ions.
The process of the present invention is expediently carried out in an aqueous medium, if appropriate, admixed with a water-miscible organic solvent. Suitable organic solvents include 1,4-dioxane, tetrahydrofuran, ethyleneglycol and dimethoxyethylether. 1,4-Dioxane is preferred.
The proportion of water to the organic solvent is in the range of 1:4 by volume, preferably in the range of 1:1 by volume.
The temperature of the reaction is not critical. The reaction is operative over a wide temperature range, that is, from 30.degree. C. to the reflux temperature of the reaction mixture. Lower temperatures can be used, but are of no advantage, since the reaction appears to proceed at lower temperatures.
The reaction of the present process is preferably carried out at a temperature from about 60.degree. C. to the reflux of the reaction mixture and most preferably at a temperature of from about 80.degree. C. to the reflux.
In accordance with the process of the present invention, the compounds of formula II or III are generally reacted with the formaldehyde agent in a molar ratio of from 1:1 to 1:4. A molar ratio of from 1:2.5 to 1:3 is preferred.
As previously mentioned, when the compounds of formula II are used as the reactants in the present process, the reaction is advantageously affected by the addition of alkali to the reaction system.
A stoichiometric amount or an excess of the alkali is generally required for this purpose. The molar ratio of the compounds of formula II to the alkali reactant varies depending on the type of bases employed. For instance, when an alkali metal base is employed, the molar ratio of the compounds of formula II to the alkali is from 1:1 to 1:3. A molar ratio of from 1:1.5 to 1:2 is preferred. When an alkali earth metal is used as the alkali source, the molar ratio of the compounds of formula II to the alkali is from 1:0.5 to 1:2. A molar ratio of from 1:0.7 to 1:1 is preferred.
In one embodiment of the process of the present invention, in which the compounds of formula III is reacted with the formaldehyde agent in an aqueous medium, the reaction is expediently carried out, optionally, in the presence of an alkali as hereinabove mentioned. The amount of alkali used for this purpose is from about 0.1 to about 1.0 mole per mole of the compounds of formula III.
The compounds of formula II may be prepared by methods known per se. (See. Chem. Ber. 91,988,1958). They can be obtained by condensing a 2-chloroacetoacetic acid ester with formamide.
The compounds of formula III may be prepared by simply treating the compounds of formula II with stoichiometric amounts of the bases indicated above.
The following examples further illustrate the present invention, but they are not construed to limit the scope of the invention.